CN103509006B - Methanesulfonic acid fluorine imatinib crystal formation and its production and use - Google Patents
Methanesulfonic acid fluorine imatinib crystal formation and its production and use Download PDFInfo
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- CN103509006B CN103509006B CN201210203179.1A CN201210203179A CN103509006B CN 103509006 B CN103509006 B CN 103509006B CN 201210203179 A CN201210203179 A CN 201210203179A CN 103509006 B CN103509006 B CN 103509006B
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- Prior art keywords
- crystal formation
- methanesulfonic acid
- acid fluorine
- fluorine imatinib
- imatinib
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention discloses a kind of methanesulfonic acid fluorine imatinib crystal formation and its production and use, its XRD characteristic peak is as it is shown in figure 1, its preparation method includes, with acetone solution methanesulfonic acid fluorine imatinib, then crystallize under the conditions of 0～10 DEG C, finally filtering to obtain target crystal formation.
Description
Technical field
The present invention relates to a kind of methanesulfonic acid fluorine imatinib crystal formation, its preparation method, its drug regimen
Thing and pharmaceutical applications thereof.
Background technology
Suffer from the patient of chronic myelogenous leukemia, have 95% to be above due to chromosome translocation,
Produce BCR-ABL fusion protein, cause high expressed ABL tyrosine to activate enzymatic activity, produce
A large amount of abnormal white cells.
In prior art, being used for treating chronic myelogenous leukemia medicine has recombinant interferon a-2a,
Cytosine arabinoside, homoharringtonine and imatinib.Imatinib mesylate (imatinib) is that treatment is slow
Property myelogenous leukemia key agents, cure mechanism be by suppression BCR-ABL activity thus
The propagation of anticancer, goes back cancer cell specific induction of apoptosis simultaneously；The patient of 95% is taking medicine one to three
Onset after Yue, cancerous cell reduces, and blood cell number returns to normal value.(she replaces by horse imatinib mesylate
Buddhist nun) be first based on human genome research determine targeted kinase and adjustment signal conduction
Medicine, is an important breakthrough in scientific research history.Within 2002, its sales volume is 6.15 hundred million dollars,
2003 annual sales amounts break through 1,000,000,000 dollars, rank among " best-selling drugs " ranks.But, send out in recent years
The many chronic myelogenous leukemia patients now taking imatinib mesylate create drug resistance.At most cases
Under, the generation of drug resistance is because BCR-ABL and there occurs variation, causes the structural change of enzyme,
Make the imatinib mesylate can not be in connection.
By research imatinib mesylate and the crystal structure of the kinase whose interaction of ABL, find this kinases
There is the important combination sublocus that an imatinib mesylate does not use.Methanesulfonic acid fluorine imatinib is at lattice
Suitable group is introduced to improve compound and kinase whose adhesion on the architecture basics defended of row,
Expectation simultaneously improves the adhesion of kinase mutant type.By methanesulfonic acid fluorine imatinib antitumor action
Mechanism Study finds, methanesulfonic acid fluorine imatinib suppresses intracellular BCR-ABL tyrosinase activity ratio
Strong about 30 times of imatinib mesylate.
As " me too " medicine of imatinib mesylate, methanesulfonic acid fluorine imatinib is also for BCR-ABL
Design.Being compared to imatinib mesylate, methanesulfonic acid fluorine imatinib structurally introduces suitable group
Can improve and kinase whose adhesion, and be expected to improve the adhesion to kinase mutant type.With
Time treatment chronic myelogenous leukemia in terms of, the drug effect of methanesulfonic acid fluorine imatinib will be apparently higher than lattice
Row are defended, and therefore have the most wide market potential.
Drug crystal forms research and the research and development of medicine solid-state have very important meaning in pharmacy industry.Medicine
Thing molecule generally has different solid forms, including salt, and polycrystalline, eutectic, amorphous, water
Compound and solvate；The different crystal forms of same drug molecule, at crystal structure, stability,
The properties such as productibility and bioavailability there may be significant difference, thus directly affects
The curative effect of medicine and exploitability.Therefore, any one drug research and development, it is required for carrying out entirely
The screening polymorph of plane system, finds crystal formation as much as possible, then uses various solid-state approach
These crystal formations are carried out in-depth study, thus finds the crystal formation being best suitable for exploitation.
Summary of the invention
It is an object of the invention to provide the crystal formation of a kind of methanesulfonic acid fluorine imatinib, its XRD data
As shown in Figure 1.
Another object of the present invention is to provide the preparation side of above-mentioned methanesulfonic acid fluorine imatinib crystal formation
Method, including:
1) with acetone solution methanesulfonic acid fluorine imatinib；
2) crystallize under the conditions of 0～10 DEG C, and
3) target crystal formation is filtered to obtain.
Wherein, recrystallization temperature preferably 5 DEG C.
Another object of the present invention is to provide a kind of drug regimen treating chronic myelogenous leukemia
Thing, its contain the above-mentioned formic acid acid fluorine imatinib crystal formation of therapeutically effective amount as effective ingredient and
Pharmaceutically acceptable carrier.
Another object of the present invention is to a kind of above-mentioned methanesulfonic acid fluorine imatinib crystal formation is provided or controls
The pharmaceutical composition treating chronic myelogenous leukemia is used for treating chronic myelogenous leukemia medicine in preparation
In purposes.
Methanesulfonic acid fluorine imatinib crystal formation stable in properties provided by the present invention, favorable repeatability, suitable
Composite medicine is developed.
Accompanying drawing explanation
Fig. 1 is the XRD figure spectrum of methanesulfonic acid fluorine imatinib crystal formation.
Detailed description of the invention
Embodiment 1
Methanesulfonic acid fluorine imatinib 1.0g and acetone 3.0ml is placed in reaction bulb, is heated to backflow,
After being completely dissolved, stirring is cooled to 10 DEG C, constant temperature crystallize 24 hours, filters, is vacuum dried
To target crystal formation, confirm its structure through accompanying drawing 1.
Embodiment 2
Methanesulfonic acid fluorine imatinib 1.5g and acetone 6.0ml is placed in reaction bulb, is heated to backflow,
After being completely dissolved, stirring is cooled to 5 DEG C, constant temperature crystallize 24 hours, filters, is vacuum dried
To target crystal formation, confirm its structure through accompanying drawing 1.
Embodiment 3
Methanesulfonic acid fluorine imatinib 2.0g and acetone 8.0ml is placed in reaction bulb, is heated to backflow,
After being completely dissolved, stirring is cooled to 20 DEG C, constant temperature crystallize 24 hours, filters, is vacuum dried
To target crystal formation, confirm its structure through accompanying drawing 1.
Experimental example 1 stability experiment
| Project | Epimer | Maximum unknown single miscellaneous | The most miscellaneous |
| Standard specifies | ≤0.8% | ≤0.15% | ≤1.5% |
| 0M | 0.08 | 0.07 | 0.27 |
| 3M | 0.08 | 0.07 | 0.28 |
| 6M | 0.08 | 0.07 | 0.29 |
| 9M | 0.08 | 0.07 | 0.29 |
| 12M | 0.08 | 0.07 | 0.28 |
Conclusion: stability of crystal form provided by the present invention is good.
Claims (5)
1. a methanesulfonic acid fluorine imatinib crystal formation, its XRD figure is composed as shown in Figure 1.
2. a preparation method for methanesulfonic acid fluorine imatinib crystal formation according to claim 1,
Including:
1) with acetone solution methanesulfonic acid fluorine imatinib；
2) crystallize under the conditions of 0～10 DEG C, and
3) target crystal formation is filtered to obtain.
The preparation method of methanesulfonic acid fluorine imatinib crystal formation the most according to claim 2, wherein
Described recrystallization temperature is selected from 5 DEG C.
4. treating a pharmaceutical composition for chronic myelogenous leukemia, it contains therapeutically effective amount
Formic acid acid fluorine imatinib crystal formation as claimed in claim 1 as effective ingredient and pharmaceutically may be used
The carrier accepted.
5. a methanesulfonic acid fluorine imatinib crystal formation according to claim 1 or according to right
Require that the pharmaceutical composition of the treatment chronic myelogenous leukemia described in 4 is used for treating chronic in preparation
Purposes in myelogenous leukemia medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210203179.1A CN103509006B (en) | 2012-06-19 | 2012-06-19 | Methanesulfonic acid fluorine imatinib crystal formation and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210203179.1A CN103509006B (en) | 2012-06-19 | 2012-06-19 | Methanesulfonic acid fluorine imatinib crystal formation and its production and use |
Publications (2)
| Publication Number | Publication Date |
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| CN103509006A CN103509006A (en) | 2014-01-15 |
| CN103509006B true CN103509006B (en) | 2016-11-16 |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974139B (en) * | 2014-04-04 | 2019-09-06 | 江苏豪森药业集团有限公司 | Methanesulfonic acid fluorine imatinib novel crystal forms and preparation method thereof and medical usage |
| CN107176937B (en) * | 2017-04-20 | 2019-08-30 | 沈阳药科大学 | α-pyranone phomone D and its preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1972917B (en) * | 2004-12-31 | 2010-08-25 | 孙飘扬 | Aminopyrimidine compounds and their salts, process for preparation and pharmaceutical use thereof |
| CN102796079A (en) * | 2011-05-27 | 2012-11-28 | 江苏豪森医药集团连云港宏创医药有限公司 | Method for preparing flumatinib mesylate |
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2012
- 2012-06-19 CN CN201210203179.1A patent/CN103509006B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1972917B (en) * | 2004-12-31 | 2010-08-25 | 孙飘扬 | Aminopyrimidine compounds and their salts, process for preparation and pharmaceutical use thereof |
| CN102796079A (en) * | 2011-05-27 | 2012-11-28 | 江苏豪森医药集团连云港宏创医药有限公司 | Method for preparing flumatinib mesylate |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis,Crystal Structure,and Spectral Characteration of Flumatinib Mesylate;GANG Xu et al.;《Synthetic Communications》;20100805;第40卷(第17期);2564-2570 * |
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Address after: 222006 Jiangsu province Lianyungang Kaitai Dapu Road Industrial Area Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222006 Jiangsu province Lianyungang Kaitai Dapu Road Industrial Area Applicant before: Jiangsu Hansoh Pharmaceutical Group Lianyungang Hongchuang Medical Co., Ltd. |
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Effective date of registration: 20160314 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222006 Jiangsu province Lianyungang Kaitai Dapu Road Industrial Area Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. |
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